Pharmacologically active compounds

ABSTRACT

A new class of derivatives of the ethyl ester of fluoroacetic acid is described and some methods for their preparation are reported. The compounds have a pharmacological interest, because of their marked antiinflammatory activity.

United States Patent Cavalleri et al. 451 Oct, 17, 1972 1PHARMACOLOGICALLY ACTIVE 3,476,803 11/1969 Pine ..260/522 COMPOUNDS3,257,420 6/1966 Szarvasi ..260/522 3,227,736 l/l966 Tschesche et al...260/476 [72] l f" 2,535,086 12/1950 Moffett et al ..260/522 mm W 1 964516 6/1934 Jaeger ..260/476 Nmmbre, 1:925:59o 9/1933 Jaeger ..260/476Tesla 51mm 1,892,766 1/1933 Jaeger ..260/522 callo, Ticino, Switzerland;Giulio Maffii, Via Gioberti 2, Milan, Italy FOREIGN PATENTS ORAPPLICATIONS [22] Filed: Aug. 5, 1968 1,374,665 8/1964 France ..260/476[21] Appl. No.: 750,009 OTHER PUBLICATIONS Chemical Abstracts Vol. 57,Co]. 16645f, 1962 Belet- [30] Foreign Application Priority Data skaya etal.

Aug. 14, 1967 Great Britain ..37,l97/67 Chem" My 1967 528'529 Chapman etPrimary Examiner-Lorraine A. Weinberger [52] US. Cl ..260/473 R,260/346.2, 260/469, Assistant Examiner R weissberg 260/476 424/308Attorney-Joseph Hirschmann [51] Int. Cl ..C07c 69/76, C07d 5/44 [58]Field of Search ..260/476, 522, 476 R, 469, 57 ABSTRACT 473 R 1 a A newclass of derivatives of the ethyl ester of [56] References Citedfluoroacetic acid is described and some methods for their preparat1onare reported. The compounds have a UNITED STATES PATENTS pharmacologicalinterest, because of their marked antiinflammatory activity. 3,557,1891/1971 Eue et al. 260/476 R 3,567,742 3/1971 Cavalleri et al ..260/475 X2 Claims, NoIJrarvings PHARMACOLOGICALLY ACTIVE co oum s This inventionis concerned with a new class of compounds and with the methods forpreparing them. More particularly the compounds of the invention arerepresented by the following general formula:

R Cl-lF COOC H wherein R is a member of the class consisting of aryl,dibenzofuranyl, and a radical having the formula wherein R has the abovesignificance, is reacted with an equimolecular amount of an alkali metalhydroxide in' absolute ethanol at a room temperature.

The symbol X represents an alkali metal. B. The process consists incontacting a solution of a compound, having the general formula whereinR has the above significance and Me represents an alkali metal atom, inan organic, inert and anhydrous solvent, with a cationic, ion-exchangeresin at a temperature of about 5075.

OOMe

It 1F COC2H5 resin C. A compound of thegeneral formula The compounds ofthe invention proved interesting for their antiinflammatory activity.This property was evaluated through the known carrageenin induced edematest in rats. We used for our experiments Wistar female rats of 120-150g. body weight. g

The drugs to be tested were administered by gastric gavage, dissolved orsuspended in a 10 percent aqueous solution of acacia gum, contained in avolume of 1 ml. per 100 g. body weight, followed immediately by tapwater to a total of 5 ml. per rat.-

The controls were given only percent acacia gum solution and water.

As phlogistic agent, a 1 percent carrageenin suspen- I sion in sterilephysiological sodium chloride solution was used, injecting 0.05 ml. ofit under the plantar aponeurosis of the hind right paw, 1 hour after theoral treatment. Immediately thereafter the volume of the injected pawwas measured by means of a plathysmograph and the measure repeated 3hours later.

The increase in foot volume represents the degree of the developededema.

- By comparing the edema of the treated animals with that of thecontrols, it is possible to evaluate the effectiveness of the testeddrugs. The following table 1 reports the results obtained with somecompounds of the invention, expressed as percent decrease of the edemain the treated animals with respect to the controls. The toxicities arealso given for a better evaluation of the safety of the compounds.

TABLE 1 Compound of LD mg/kg Dose mg/kg Carrageenin example i.p., inmice es, in rats edema Decrease I00 4L6 5 500 m0 51.3 so 37.5

The following non limitative examples'illustrate the invention.

EXAMPLE 1 Preparation of ethyl fiuoro(p-methoxyphenyl)- acetate.

1. According to method A.

To a solution of 1.3 g. (4.5 mmole) of diethylfluoro(p-methoxyphenyl)-malonate, in ml. of absolute ethanol, 8.5 ml. ofa 3 percent ethanolic solution of potassium hydroxide are added during 6hours at room temperature. At the end of the reaction, 1 liter ofdiethyl ether is added and the mixture is allowed to stand overnight. Aprecipitate consisting of the monopotassium salt of the monoethylfiuoro(pmethoxyphenyl)-malonate is formed. After filtering, the solutionis concentrated to dryness. The residue is distilled and the fractionboiling at 100l05C/0.2 mm. is collected.

2. According to method B.

An amount of 340 ml. of amberlite IR (H), previously washed withabsolute ethanol, is transferred into a water-jacketed glass tube, 60cm. long and of 3 cm. inside diameter, and hot absolute ethanol isadded,

until the .top of the column is covered by the liquid. While water at60C is circulated into the jacket, 'a hot solution containing g. ofmonopotassium salt of the monoethyl fluoro(p-methoxyphenyl)-malonate dissolved in 1.4 liters of absolute ethanol, is slowly poured onto the topof the column, collecting at the same time the eluate. When all thesolution has beenadded, the column is washed with hot ethanol, and theeluate concentrated in vacuo at a temperature not exceeding 50C. Theresidue is taken up with diethyl ether and quickly washed with a 10percent aqueous solution of sodium bicarbonate. The organic phaseisdried over sodium sulphate and the solvent removed with the aid ofvacuum in an evaporator. The residue is distilled at 100l05C/0.2 mm.,avoiding overheating. A colorless oil is obtained, consisting of ethylfluoro(p-methoxypheny-U-acetat'e. Yield 77,8 percent; n 1,5133. Analysisv r Calcd. for c n ro c, 62,25; l-1,,6,17; F,'8,95

Found C; 62,l7;l-1,'6,30;F, 8,76 3. According to method C.

To a solution of 11.65 g. (55 mmole) of ethyl-pmethoxymandelate in 150ml. of anhydrous methylene chloride, 20.8 g..' (0.1 1 mole) of2-chloro-1,l,2-

trifluoro-triethylamine are added. The solution is allowed to standovernight at 5C, then for 5 more hours at room temperature. It is thenwashed with a saturated sodium carbonate solution, and successively withwater, dried over anhydrous sodium sulphate and concentrated. A residueis obtained which is distilled in vacuo, collecting the fraction boilingat l00l06 C/0.2 mm. An amount of 8.6 g. of ethylfluoro(pmethoxyphenyl)-acetate is obtained. Yield 73.8 percent. a

Analysis Calcd. for C, H,' FO C, 62,25; H, 6,17; F, 8,95 Found C, 61,59H, 5,80; F, 8,61

EXAMPLE 2 Preparation of ethyl p-ethoxyphenyl (fluoro)-acetate 2.According to method A.

To a solution of 4.3 g. (14 mmole) of diethyl pethoxyphenyl(fluoro)-malonate-in ml. of absolute ethanol 28ml. of a 3 percentethanolic solution of potassium hydroxide (14 mmole) are added during 7hours at room temperature. Then, 3 liters of diethy ether are added andthe mixture is allowed to stand overnight. A precipitate ofmonopotassium salt of the monoethyl p-ethoxyphenyl (fluoro)-malonate isformed and filtered off. The solution is concentrated to drynessinvacuo. Theresidue is distilled, collecting the fraction boiling atl00-l05C/0.2 mm.

2) According to method B.

A solution of 10 g. (32 mole) of the monopotassium salt of the monoethylp-ethoxyphenyl (fluoro)- malonate in 500 ml. of hot absolute ethanol, ischromatographed under the same conditions and using the same apparatusdescribed in example 1. The eluate is concentrated in vacuo at atemperature not exceeding 40C. The residue is taken up with diethylether, washed with a 10 percent solution of sodium bicarbonate and driedover sodium sulphate. The solvent is evaporated and the residue isdistilled in vacuo, co1lecting the fraction boiling at 105'-l07C/0.2 mm.A colorless oilis obtained consisting of ethyl p -ethox- 4 yphenyl(fluoro)-acetate. Yield 87 percent; 9 1.5095. Analysis Calcd. for c nro, C, 63,69; H, 6,68; F,- 8,39 Found C, 63,59; H, 6,88; F, 8,31 9

EXAMPLE 3 the precipitated salts the solution isconcentrated in vacuo ata temperature not exceeding 40C. The residue is distilled in'vacuo andthe fraction boiling at 93101 "C/0.2 mm. is collected. An oil isobtained,

consisting of ethyl fluoro(p-isobutylphenylyacetate.

Yield 74 percent; n =1,4958.

Analysis Calcd. for C H F0, C, 70,56; H, 8,03; F 7,97 Found C, 70,40; H,8,20; F, 7,85

EXAMPLE 4 Preparation of ethyl fluoro( l-naphthyl)-acetate lfAccordingto method A. v 7

To a solution of 4.3 g. (14 mmole) of diethyl fluoro(l-naphthyD-malonatein 130 ml. of absolute ethanol 26.5 ml. of a 3 percent ethanolicsolution of potassium hydroxide are added at room temperature during 7hours. A volume of 3 l. of diethyl ether is added and the mixture isallowed to stand overnight. The precipitated salts are filtered off,then the filtrate is concentrated to dryness in vacuo at a temperaturenot exceeding 40C. An oily residue is obtained. 2. According to methodB.

It is prepared working under the same conditions described in example 1.A quantity of 12.7 f. (40 mmole) of the monopotassium salt of themonoethyl fluoro(1-napthyl)-malonate, dissolved at 40C in 1.1

liters of absolute ethanol, are passed through a column of 340 ml. ofamberlite IR (H). The eluate is concentrated and the residue taken upwith diethyl ether. The ether solution is washed with a 10 percentsolution of sodium bicarbonate, dried over sodium sulphate andconcentrated. The residue is distilled in vacuo, collecting the fractionboiling at 120-125C/0.2 mm. An oil is obtained consisting of ethylfluoro( l-naphthyl)- acetate. Yield 84 percent; n =1,5803. Analysis a ICalcd. for c l-l FO C, 72,39; H, 5,64; F, 8,18 Found C, 72,25; H, 5,87F, 8,18

To a solution of 9.15 g. (26,5 mole) of diethyl 2- dibenzofuranyl(fluoro)-malonate, in 250 m1. of ab solute ethanol, 48.5 ml. of a 3percent potassium 1. A compound possessing antiinflammatory activity andof the formula RCHFCO0C +l-l wherein R is (p-isobutylphenyl).

2. A compound possessing antiinflammatory activity and of the formulaR-CHF-COOC +H wherein R is (p-methoxyphenyl).

UNITED STATES PATENT OFFICE QERTWICATE OF CORRECTEON Dated October 17,1972 Patent No. 3 699,151

n Bruno Cavalleri, Elvio Bellasio, Emilio Testa, Giulio Maffii.

It is certified that error appears 'in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In Claims 1 and 2 the formula should read:

Y R-cHF-cooc H Signed and sealed this 18th day of December 1973c (SEAL)Attest:

RENE D. TEGTW'EYER EDWARD M. FLETCHER, JR.

' Acting Commissioner of Patents At te sting Officer

2. A compound possessing antiinflammatory activity and of the formula R-CHF-COOC2 H5 wherein R is (p-methoxyphenyl). 